The overall goal of this Program Project is to develop novel therapeutic approaches to human myeloid leukemias based on new insights into molecular genetics and host immune responses to leukemia. To achieve this goal, we have assembled a team of basic scientists, immunologists, clinical scientists, leukemia specialists, and biostatisticians who bring broad expertise t the Program. There are 5 highly interactive Projects supported by 2 Cores that will focus on strategies to improve our success rate in treating myeloid leukemias. These strategies include gene discovery, characterization of the transforming properties of leukemia-causing genes, and validation in cell culture and vertebrate models of transformation. These studies in turn will provide a foundation for preclinical and clinical testing of drugs that inhibit validated target genes, as well as preclinical and clinical testing of immunotherapeutic approaches to leukemia. In Project 8, Dr. Griffin will study tyrosine kinase oncogenes in acute myeloid leukemias, with a focus on activating mutations in FLT3; characterize mechanisms of kinase activation and signal transduction; and access inhibitors of tyrosine kinases as potential therapeutic agents. Dr. Gilliland will focus in Project 1 on murine models of leukemia mediated by activating mutations in FLT3, and use these models to test the hypothesis that acute myeloid leukemias are the consequence of cooperating mutations that enhance viability of cells, and impair differentiation. The murine models will be used in preclinical studies to test novel therapeutic agents, including FLT3 kinase inhibitors. Project 9 is led by Dr. Tenen, who will characterize the role of mutations in hematopoietic transcription factors in myeloid leukemia, with a focus on PML/RARa and C/EBPa. The power of forward genetic approaches in zebrafish will be exploited by Dr. Look in Project 10, who will identify and characterize novel genes that contribute to pathogenesis of leukemia. Project 7, under the direction of Dr. Dranoff, will test novel immunotherapeutic approaches in clinical trials, with a focus on vaccines targeted to newly discovered leukemia antigens. In the second specific aim of Project 7, Dr. Ritz will extend this approach using strategies to identify novel leukemia specific antigens. Dr. Stone, in the third specific aim, will develop and implement clinical trials of AML based on specific inhibitors of FLT3. These projects will be supported by a Clinical Core led by Dr. Stone, and all Projects will have extensive interactions and support from the Biostatistics Core under the direction of Dr. Neuberg. The thrust of this Program is to take full advantage of our rapidly expanding understanding of the molecular pathogenesis of leukemias and host immune responses to develop curative approaches to myeloid leukemias.